A Conserved Sequence Approach for MS Association Studies

MS 关联研究的保守序列方法

• 批准号: 7160493
• 负责人: DOUGLAS P MORTLOCK
• 金额: $ 7.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160493
• 关键词: 1q43; Affect; Antigens; Autoimmune Process; Autoimmune Responses; Axon; Binding; Biological Assay; Candidate Disease Gene; Characteristics; Chromosomes; Cicatrix; Classification; Clinical; Complex; Conserved Sequence; Data; Data Set; Databases; Demyelinations; Disease; Environmental Exposure; Etiology; Exhibits; Family; Functional disorder; Genes; Genetic; Genomics; Genotype; Goals; HLA Antigens; Hereditary Disease; Heterogeneity; Histocompatibility Antigens Class II; Human; Human Chromosomes; Individual; Inflammatory; Location; Major Histocompatibility Complex; Measures; Modeling; Multiple Sclerosis; Mus; Myelin Proteins; Myelin Sheath; Nerve; Neuraxis; Neurodegenerative Disorders; Peptides; Phenotype; Play; Polygenic Traits; Population; Predisposition; Process; Rattus; Regulatory Element; Research; Research Personnel; Research Proposals; Role; Scanning; Score; Sequence Analysis; Susceptibility Gene; T-Lymphocyte; Testing; Thinking; Time; Tissues; United States; Validation; Variant; base; comparative; cost; follow-up; genetic association; genetic pedigree; genome sequencing; interest; novel strategies; success; tool

DESCRIPTION (provided by applicant): Genomic linkage screens have served as the workhorse of genetic studies for complex diseases over the past decade. Despite the success of these screens in identifying regions of interest for complex diseases, follow-up of linkage regions with candidate gene approaches have largely failed to identify causative loci. The goal of the current proposal is to employ a novel approach to investigate genetic association on the scale of a linkage peak for a complex genetic disease. Using multiple sclerosis (MS) as a model, this approach focuses on selection of SNP markers located in multi-species conserved sequences identified using new comparative sequence analysis tools. As for many complex genetic diseases, researchers have conducted numerous genomic screens in an attempt to identify regions potentially harboring MS loci. Thorough follow-up of all candidate genes in all regions of linkage for MS has proven to be prohibitive in terms of both time and cost, and has ultimately failed to identify susceptibility genes outside of the major histocompatibility complex. It is likely that these candidate gene studies for MS have been hampered by the incomplete identification and characterization of genes or regulatory elements that are directly related to disease pathophysiology. This research proposal aims to formulate a systematic approach to expedite the follow-up of positional candidate regions identified through linkage studies and apply this approach to a genomic region that demonstrates significant linkage to MS. We hypothesize that by focusing on SNPs located in evolutionarily conserved regions, we can increase the likelihood of detecting variants that are associated with disease. The specific aims of the proposed project are to: 1.) Prioritize SNP markers for an MS association study on chromosome 1q43 based on conservation between human, mouse, rat, and chick genome sequences; 2.) Measure association between a dense population of SNPs located in conserved regions of interest on chromosome 1q43 and a dataset of ~200 multiplex and ~600 simplex MS families. The novel approach for follow-up of linkage studies proposed in this study will increase the likelihood of successfully identifying a genetic factor in the 1q43 region and will potentially demonstrate a paradigm that expedites the search for genes in MS and other complex diseases.

描述（由申请人提供）：在过去的十年中，基因组连锁筛选已成为复杂疾病遗传学研究的主力。尽管这些筛选在识别复杂疾病的感兴趣区域方面取得了成功，但使用候选基因方法对连锁区域进行后续追踪在很大程度上未能识别致病位点。当前提案的目标是采用一种新方法来研究复杂遗传疾病连锁峰范围内的遗传关联。该方法以多发性硬化症 (MS) 作为模型，重点选择位于使用新的比较序列分析工具鉴定的多物种保守序列中的 SNP 标记。对于许多复杂的遗传疾病，研究人员进行了大量的基因组筛选，试图找出可能含有多发性硬化症基因座的区域。事实证明，对 MS 连锁的所有区域中的所有候选基因进行彻底的随访在时间和成本方面都是令人望而却步的，并且最终未能鉴定出主要组织相容性复合体之外的易感基因。这些多发性硬化症的候选基因研究可能因与疾病病理生理学直接相关的基因或调控元件的不完整识别和表征而受到阻碍。本研究提案旨在制定一种系统方法，以加快对通过连锁研究确定的位置候选区域的跟进，并将该方法应用于与 MS 显着连锁的基因组区域。我们假设，通过关注位于进化保守区域的 SNP，我们可以增加检测与疾病相关的变异的可能性。该项目的具体目标是： 1.) 基于人类、小鼠、大鼠和鸡基因组序列之间的保守性，优先考虑染色体 1q43 上 MS 关联研究的 SNP 标记； 2.) 测量位于染色体 1q43 上感兴趣的保守区域中的密集 SNP 群体与约 200 个多重 MS 家族和约 600 个单一 MS 家族的数据集之间的关联。本研究中提出的连锁研究后续新方法将增加成功识别 1q43 区域遗传因子的可能性，并有可能展示一种加速多发性硬化症和其他复杂疾病基因搜索的范例。